Obesity and low bone quality (osteopenia/osteoporosis) are prevalent public health issues worldwide, contributing significantly to metabolic disease and fracture risk. A growing body of evidence suggests that environmental exposures are contributing to the incidence and severity of these pathological conditions. Both legacy Superfund chemicals (organotins, polychlorinated biphenyls (PCB)) and Superfund chemicals of emerging concern (organophosphate flame retardants) have been recognized as metabolic and bone disruptors. While a strong physiological coupling of obesity and osteoporosis may seem unlikely, the recent discoveries of fat and bone regulatory crosstalk suggest that they share common origins. Adipose and bone tissue each contain multipotent cells whose differentiation and fate are regulated by common nuclear receptors. One such nuclear receptor is the peroxisome proliferator activated receptor ? (PPAR?), an essential regulator of adipocyte differentiation and function and a negative regulator of bone homeostasis. Critical gaps in our knowledge prevent our understanding of the potential for environmental PPAR? activators to contribute to development of disease, including: 1) how environmental PPAR? ligands disrupt metabolic health, whereas therapeutic PPAR? ligands used to treat type 2 diabetes improve metabolic health; 2) whether developmental exposures program both adipose and bone dysfunction in adulthood, and 3) how environmental PPAR? activators interact with other classes of adipose- and bone-disrupting chemicals (e.g. PCBs). Our novel and compelling preliminary data show that that tributyltin (TBT) alters adipose and bone differentiation in vitro and adipose and bone homeostasis in vivo, through its interaction with PPAR? and with the retinoid X receptor (RXR). We identified a novel PPAR? ligand, the common organophosphate flame retardant triphenyl phosphate (TPhP), which coordinately enhances adipocyte differentiation and suppresses bone formation in vitro. TPhP stimulates adipose accumulation and hepatic steatosis following adult exposures, and lipodystrophy and systemic inflammation following perinatal exposures. TPhP and TBT activate PPAR?, but also induce adipocyte transcriptomes that are distinct from those induced by a therapeutic PPAR? ligand. Here, we propose to investigate the hypothesis that TPhP and TBT selectively modulate PPAR??s activation and function to compromise adipose and bone homeostasis. We will address three Specific Aims: 1) to determine how early life exposures to TPhP and TBT impact adipose and bone homeostasis in adulthood; 2) to define how selective activation of PPAR? by TPhP and TBT modifies adipocyte function, and 3) to define the roles of PPAR? and RXR in disruption of osteoblast/osteoclast function and crosstalk by TPhP and TBT. Collectively, our work will enhance our knowledge of the physiological processes driving adipose and bone dyshomeostasis and of how early life toxicant exposures exacerbate risk of developing disease, contributing to our ability to minimize/prevent chronic disability caused by exposure to Superfund chemicals.